It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938), the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain comparatively large reductions in plasma cholesterol with very few adverse effects.
In addition to the natural product lovastatin, there have been several semi-synthetic and totally synthetic HMG-CoA reductase inhibitors approved for prescription use, including simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin sodium salt (LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin calcium salt (LIPITOR®; see U.S. Pat. No. 5,273,995) and cerivastatin sodium salt (BAYCOL®; see U.S. Pat. No. 5,177,080). Still other HMG-CoA reductase inhibitors are known to be in development, for example pitavastatin also referred to as NK-104 (see PCT international publication number WO 97/23200); and rosuvastatin also known as ZD-4522 (CRESTOR®; see U.S. Pat. No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp. 511-513). The structural formulas of these and additional HMG-CoA reductase inhibitors, are described at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996). The HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open-acid, and are often referred to as “statins.” An illustration of the lactone portion of a statin and its corresponding open-acid form is shown below.

Salts of the dihydroxy open-acid can be prepared, and in fact, as noted above, several of the marketed statins are administered as the dihydroxy open acid salt forms. Lovastatin and simvastatin are marketed worldwide in their lactonized form. Lovastatin is shown as structural formula I, and simvastatin is shown as structural formula II, below.

The lactonized forms of the statins are not active inhibitors of HMG-CoA reductase, but the dihydroxy open acid forms are. It is known that condensation of the dihydroxy open acid form of statins to the corresponding lactonized form occurs under acidic conditions, that is at about pH 4 or under. Therefore, due to the low gastric pH of the stomach, a statin conventionally administered by oral dosing in its lactone form will remain largely in its lactone form in the stomach. The vast majority of the drug will still be in the lactone form at the time of absorption from the intestine following oral dosing with the lactone. After absorption, the lactone enters the liver and it is in the hepatocytes that the lactone can be metabolized to the active open acid form, a reaction catalyzed by two hepatic esterases or “lactonases,” one which is in the cytosolic and the other in the microsomal fraction. Once in the blood there is an additional plasma esterase that can also hydrolyze the lactone to the open acid. There may be some minimal chemical, i.e., non-enzymatic, hydrolysis that occurs in blood or in the liver; however, at the pH in blood and liver, there should not be any lactonization, i.e., conversion of open acid back to the lactone.
Since becoming available, millions of doses of simvastatin have been administered and these drugs have developed an excellent safety record. In fact, simvastatin has been administered to over 20 million patients worldwide in the past 11 years and has been demonstrated to be remarkably safe. However, as noted in the Physician's Desk Reference (PDR), occasional instances of myopathy have been associated with the use of all statins, including simvastatin, which manifest as muscle pain or weakness associated with grossly elevated creatine kinase, and more rarely instances of rhabdomyolysis have been reported, marked by the destruction of muscle cells which enter the bloodstream. The mechanism for statin-related myopathy is currently poorly understood. The risk of myopathy may be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. It is known that many drugs, including certain statins such as simvastatin, are metabolised in the liver and intestine by the cytochrome P450 isoform 3A4 (CYP3A4) enzyme system. The very low risk of myopathy may be increased when a CYP3A4-metabolized statin is used in combination with a potent inhibitor of this metabolic pathway which can raise the plasma levels of HMG-CoA reductase inhibitory activity. Such potent inhibitors include cyclosporine; the azole antifungals, itraconazole and ketoconazole; the macrolide antibiotics, erythromycin and clarithromycin; HIV protease inhibitors; the antidepressant nefazodone; and large quantities of grapefruit juice (>1 quart daily).
It is also known that concomitant drug therapy with simvastatin and gemfibrozil, a member of the class of fibric acid derivatives (fibrates) which shows only minimal inhibition of in vitro CYP3A4 functional activity, increases the risk for myopathy. In a study involving combination treatment with simvastatin and gemfibrozil described in Backman, et al., Plasma concentrations of active simvastatin acid are increased by gemfibrozil, Clin. Pharmacology & Therapeutics, vol 68:2, 122-129 (August 2000), it was reported that gemfibrozil considerably increased plasma concentrations of open acid simvastatin, with only minimal increase in the plasma AUC (area under the curve) of parent simvastatin. The paper also stated that gemfibrozil showed no appreciable inhibitory effect on CYP3A4 mediated 1′-hydroxylation of midazolam in human liver microsomes, an in vitro assay for determining hepatic CYP3A4 activity. Therefore, since gemfibrozil is not an inhibitor of CYP3A4 in vitro, yet it increases the plasma AUC of open acid simvastatin when co-administered with simvastatin, the pharmacokinetic interaction between the two drugs is most likely via another pathway distinct from the CYP3A4 pathway.
Although the rate of occurrence of myopathy is extremely low for most statins, cerivastatin, sold in the U.S. under the tradename BAYCOL®, was recently withdrawn from the worldwide market after being linked to significantly more fatal cases of rhabdomyolysis than the other available statins. The side effect was most likely to occur when BAYCOL® was given in high doses or when it was given with the cholesterol drug gemfibrozil.
While the overall safety record for simvastatin is exceptional, it would be desirable to further optimize the safe utilization of simvastatin as well as statins in general by reducing the potential for adverse drug interactions, when the statins are co-administered with one or more additional active agents. It would also be desirable to further reduce the already low rate of occurrence of myopathy and rhabdomyolysis associated with the use of most statins. Further, it would be useful to know how cerivastatin differs pharmacokinetically from other statins in this regard in order to have a better understanding of the mechanism for statin-related myopathy. Statins are among the most widely used drugs in the world, and therefore the benefit of any further optimization of their safety profile would be significant.